Different relevance of inactivation and F468 residue in the mechanisms of hEag1 channel blockage by astemizole, imipramine and dofetilide

Abstract

The relevance of a point mutation at the C-terminal end of the S6 helix (F468) and the introduction of C-type inacti vation in the blockage of hEag1 channels by astemizole, imipra mine and dofetilide was tested. C-type inactivation decreased block by astemizole and dofetilide but not imipramine, suggest ing different binding sites in the channel. F468C mutation in creased IC50 for astemizole and imipramine but in contrast to HERG channels, only slightly for dofetilide. Together with mea surements on recovery of blocking, our observations indicate that the mechanism of hEag1 blockage by each of these drugs is dif ferent, and suggest relevant structural differences between hEag1 and HERG channels